Our proposal, Human Immunology Project Consortium (DHIPC), is based on an innovative strategy, compelling preliminary studies, and a wide network of multidisciplinary collaborations and will study the human immune responses 1) during or following dengue virus (DENV) infection, 2) before and after live attenuated DENV vaccination, using high-throughput systems biology approaches coupled with detailed clinical phenotyping in well-characterized human cohorts. The long-term goal is to develop molecular signatures that define immune response and categories/fingerprints/profiles that correlate with the outcome of infection and vaccination. We will use ?omics? technology platforms including genomics (Core B), RNAi screens (Project 3) and proteomics (Core C), and immune profiling (Core D) to study human cells from healthy donors (Project 3) and well characterized human cohorts of DENV infected children that include symptomatic versus non-symptomatic infections in dengue endemic areas (Project 1). We also include studies of live attenuated DENV vaccinations in humans (Project 2), to predict immunogenicity, and in the future correlate immune profiles determined before or soon after vaccination with protective efficacy, and also with adverse events triggered by vaccination. The data analysis and modeling core (Core E) will be the engine for translating omics data into biological insight and the data Management Dissemination Core (Core F) will act as a central repository for all data and resources generated by the Center, and ensure that these materials are readily accessible by not only other scientists in the program, but also the broader scientific community. The results of our proposed systems immunology studies will create a foundation for future hypothesis-driven research and may help develop diagnostic tools and define immune profiles correlated with outcomes of infection and vaccination. The Projects and Cores are overseen by an Administrative Core (Core A), which has an organizational structure for reporting and accountability to maintain scientific and fiscal flexibility and responsibility. Dengue disease is of great public health importance and our program has the unique opportunity to compare natural infections with live attenuated vaccines under clinical development both in vivo and ex vivo, building a new paradigm for studying other human infectious diseases in the settings of infection and vaccination.